1. Field of the Invention
This invention relates to an improved method of making unsymmetrically substituted fluorenyl compounds having strong second order nonlinear optical activities. More specifically, one step of this method further comprises the preparation of unsymmetric 2,7-disubstituted fluorenyl compounds via nucleophilic replacement of at least one of the substituents in a 2,7-disubstituted fluorenyl precursor with another functional group.
2. Prior Art
Organic polymer materials which have large second order nonlinear optical (xe2x80x9cNLOxe2x80x9d) response are of interest for optical applications including data storage, communications, and computing. Important applications include waveguides, interconnects, switches, and the like. The advantages over the conventionally employed inorganic materials, e.g., LiNbO4, in such applications include fast response time, large electro-optical response over a wide frequency range, low dielectric constant, compatibility with silicon wafer technology and others. However, because known NLO active polymers suffer from lack of long term stability under working temperature conditions, their practical utility is limited.
In our ""065 Application, we have described thermal stable fluorene-based compounds which are highly NLO active through their unsymmetrical substitution at the aromatic rings of the general formula A: 
wherein
m and n are independently integers of from 1 to 4;
R1 and R2 which are the same or different in groups Dxe2x80x94R1xe2x80x94 and Axe2x80x94R2xe2x80x94, each are optionally present and independently xe2x80x94Arxe2x80x94, xe2x80x94Arxe2x80x94Hxe2x95x90CHxe2x80x94 or xe2x80x94Arxe2x80x94Cxe2x89xa1Cxe2x80x94, where in Ar is a divalent bridging group selected from the group consisting of phenylene, biphenylene, naphthalene, and thienylene;
A is an electron accepting group selected from xe2x80x94NO2, xe2x80x94CN, xe2x80x94CO2R, xe2x80x94C(O)R, xe2x80x94SO2R, xe2x80x94SO2RF, xe2x80x94C(CN)xe2x95x90C(CN)2 or xe2x80x94CHxe2x95x90C(CN)2;
RF is xe2x80x94CpF2p+1;
p is an integer of from 1 to 10;
R is an straight, branched or cyclic aliphatic alkyl group having about 1 to 10 carbon atoms, or an aromatic group such as phenyl or naphthyl;
xe2x80x83is an electron donating group selected from xe2x80x94NH2, xe2x80x94NHR, xe2x80x94NR2, xe2x80x94OH, xe2x80x94OR, xe2x80x94SH, or xe2x80x94SR, wherein R is same as defined above;
X and Y are groups capable of partaking in polymerizations reactions and are independently selected from the group consisting of xe2x80x94H, xe2x80x94NH2, xe2x80x94NHR, xe2x80x94NR2, xe2x80x94OH, xe2x80x94OR, xe2x80x94SH, xe2x80x94SR, xe2x80x94COOH, xe2x80x94NCO, 
xe2x80x83wherein
R is same as defined above, and
y is an integer from about 1 to about 10.
As used throughout, the terms m, n, R1, R2, A, RF, p, R, D, y, X and Y are defined as described above in connection with the compounds of formula A unless otherwise indicated.
These unsymmetrically substituted fluorenyl compounds can be used to make high glass transition temperature nonlinear optical polymers. By xe2x80x9cunsymmetricalxe2x80x9d, it is meant that substituents on the two opposite phenyl rings of the fluorenyl moiety are non-identical. Some of these fluorenyl compounds can be grown into non-centrosymmetric crystals, while all of such compounds can be used as additives in host-guest polymer systems.
In U.S. patent application Ser. No. 028,921, filed Mar. 8, 1993, (pending), we have disclosed various polymers exhibiting nonlinear optical properties and high glass transition temperatures made from either the unsymmetrically substituted fluorenyl compounds or monomers described above.
In the simple case wherein both R1 and R2 are not present, formula A may be rewritten as indicated below in formula B: 
These unsymmetrically substituted fluorenyl compounds of the formula B are usually prepared from a 2,7-disubstituted fluorene derivative, preferably a 2,7-disubstituted 9-fluorenone derivative such as 2-fluoro-7-nitro-fluoren-9-one and the easily available 2,7-dinitrofluoren-9-one or its ketal, 2-(2,7-dinitro-9-fluorenyl)1,3-dioxolane. However, the replacement of a nitro group on these molecules by other functional groups is usually a low-yield, time-consuming, multi-step process which includes the reduction of the nitro group to an amine group followed by subsequent reactions. See, e.g., ""065 application, xe2x80x9cStep 2xe2x80x9d.
A nitro group has long been known to activate another functional group in the same aromatic moiety towards nucleophilic displacements (xe2x80x9cSNAr reactionsxe2x80x9d). See, e.g., Bunnett, J. F., 12 Q. Rev. Chem. Soc. 1 (1958); Miller, J., Aromatic Nucleophilic Substitution, (1968); and Terrier, F., Nucleophilic Aromatic Displacement: The Influence of the Nitro Group, (1991). In all three of these references, the activation of the nitro group is localized in the same aromatic ring containing the substituent group. By contrast, examples in which the transmission of nitro activation in one ring to another ring attached thereto are rare, if any. To our knowledge, there is no successful example of nucleophilic replacement of a substituent on one ring of a biphenyl or fluorenyl molecule activated by a nitro group attached on the opposite ring.
It would be desirable to provide an improved method for preparing these unsymmetric substituted fluorenyl compounds of general formula B in high yield, wherein the method would involve only a minimal amount of steps.
In accordance with this invention, there is provided a method for preparing unsymmetrical 2,7-disubstituted fluoren-9-one derivatives, said method comprising:
reacting a compound of the formula D: 
xe2x80x83wherein
Axe2x80x2 is the same as or different from A, and is a leaving group selected from the group consisting of xe2x80x94Br, xe2x80x94Cl, xe2x80x94F, xe2x80x94NO2, and xe2x80x94CN; 
xe2x80x83is a carbonyl or a protected carbonyl, wherein said protected carbonyl is a ketal or thio-ketal selected from the group consisting of 
xe2x80x83wherein
Rxe2x80x2 is xe2x80x94CrH2r+1;
Rxe2x80x3 is xe2x80x94(CH2)r; and
r is independently an integer of 2 or 3;
xe2x80x83A is an electron accepting group selected from the group consisting of NO2xe2x80x2xe2x80x94CN, xe2x80x94CO2R, xe2x80x94C(O)R, xe2x80x94SO2R, xe2x80x94SO2RF, xe2x80x94C(CN)xe2x95x90C(CN)2 and xe2x80x94CHxe2x95x90C(CN)2;
RF is xe2x80x94CpF2p+1;
p is an integer of from about 1 to about 10;
R is selected from the group consisting of phenyl, napthyl, and a straight, branched and cyclic aliphatic alkyl group having from about 1 to about 10 carbon atoms;
with a nucleophilic reagent in the presence of an aprotic solvent and under conditions sufficient to form a compound of the formula C 
wherein
A is as previously defined in formula D;
D is an electron donating group selected from the group consisting of xe2x80x94NH2, xe2x80x94NHR, xe2x80x94NR2, xe2x80x94OH, xe2x80x94OR, xe2x80x94SH, and xe2x80x94SR;
R is as previously defined in set A of formula D; and 
xe2x80x83is as previously defined in formula D.
Another aspect of this invention is directed to an improved process for producing unsymmetrically substituted fluorenyl compounds, said process comprising
a) reacting a compound of the formula Dxe2x80x2
xe2x80x83with a protection reagent selected from the group consisting of (CH2OH)2, 
xe2x80x83and (CH3O)3CH in the presence of an acid catalyst and a solvent under conditions sufficient to produce a protected carbonyl compound of the formula E: 
xe2x80x83wherein 
xe2x80x83is 
b) reacting said protected carbonyl compound with a nucleophilic reagent in an aprotic solvent and under conditions sufficient to produce a protected 2,7-disubstituted fluoren-9-one derivative thereof of the formula F: 
xe2x80x83wherein
D is selected from the group consisting of xe2x80x94NH2, xe2x80x94NHR, xe2x80x94NR2, xe2x80x94OH, xe2x80x94OR, xe2x80x94SH, and xe2x80x94SR;
R is selected from the group consisting of phenyl, naphthyl, and a straight, branched and cyclic aliphatic alkyl group having from about 1 to about 10 carbon atoms; and 
xe2x80x83is 
c) deprotecting said 9-carbonyl of said 2,7-disubstituted fluoren-9-one derivative in the presence of both the acid catalyst of step a and active aromatic compounds under conditions sufficient to yield a 2,7-disubstituted fluorenyl compound geminately alkylated at a 9-carbon, as shown in the formula G: 
xe2x80x83wherein
m and n are independently from about 1 to about 4;
Xxe2x80x2 and Yxe2x80x2 are independently selected from the group consisting of H, xe2x80x94NH2, xe2x80x94NR2, xe2x80x94NHR, xe2x80x94OH, xe2x80x94SR, xe2x80x94OR and xe2x80x94SH;
R is as previously defined in set D of formula F;
D is selected from the group consisting of xe2x80x94NH2, xe2x80x94NHR, xe2x80x94NR2, xe2x80x94OH, xe2x80x94OR, xe2x80x94SH, and xe2x80x94SR;
R is as previously defined in set D of formula F; and
d) optionally alkylating the compound of formula G to form a compound having formula H: 
xe2x80x83wherein
D is as previously defined in formula F;
m and n are independently from about 1 to about 4; and
X and Y are independently selected from the group consisting of xe2x80x94H, xe2x80x94NH2, xe2x80x94NHR, xe2x80x94NR2, xe2x80x94OH, xe2x80x94OR, xe2x80x94SH, xe2x80x94SR, xe2x80x94COOH, xe2x80x94NCO, 
xe2x80x83wherein
R is as previously defined in set D of formula F; and
y is an integer from about 1 to about 10;
xe2x80x83in order to obtain an unsymmetrically substituted fluorenyl compound having formula H having at least one X or Y group selected from the group consisting of xe2x80x94COOH, xe2x80x94NCO, 
Yet another aspect of this invention is directed to a process for producing unsymmetrically substituted fluorenyl compounds having the formula Z 
said process comprising:
a) reacting a compound of the formula Dxe2x80x2
xe2x80x83with a protection reagent selected from the group consisting of (CH2OH)2, 
xe2x80x83and (CH3O)3CH in the presence of an acid catalyst and a solvent under conditions sufficient to produce a protected carbonyl compound of the formula E: 
xe2x80x83wherein 
xe2x80x83is 
b) reacting said protected carbonyl compound with a nucleophilic reagent in an aprotic solvent and under conditions sufficient to produce a protected 2,7-disubstituted fluoren-9-one derivative thereof of the formula Fxe2x80x2: 
xe2x80x83wherein 
xe2x80x83is 
c) substantially fluoroalkylating said compound having formula Fxe2x80x2 with a reagent of formula RFI to form a fluoroalkyl sulfide derivative having formula Lxe2x80x2; 
xe2x80x83wherein
RF is xe2x80x94CpF2p+1;
p is an integer of from about 1 to about 10; and 
xe2x80x83is as previously defined in formula Fxe2x80x2;
d) substantially oxidizing said fluoroalkyl sulfide of step c with an oxidizing reagent to form a fluoroalkyl sulfone derivative having formula Kxe2x80x2; 
xe2x80x83wherein RF, p, and 
xe2x80x83are is as defined in Formula Lxe2x80x2;
e) further reacting the fluoroalkyl sulfone derivative of step d with a nucleophilic reagent in the presence of an aprotic solvent to form a compound having formula Mxe2x80x2
xe2x80x83wherein
RF, p, and 
xe2x80x83is as defined in Formula Lxe2x80x2, and
R is selected from the group consisting of phenyl, naphthyl, and a straight, branched and cyclic aliphatic alkyl group having from about 1 to about 10 carbon atoms;
xe2x80x83said compound having formula Mxe2x80x2 having a 9-carbonyl;
f) deprotecting said 9-carbonyl of said 2,7-disubstituted fluoren-9-one derivative of step e in the presence of the acid catalyst of step a and active aromatic compounds and under conditions sufficient to yield a 2,7-disubstituted fluorenyl compound geminately alkylated at the 9-carbon, as shown in the formula Gxe2x80x2
xe2x80x83wherein
m and n are independently from about 1 to about 4;
Xxe2x80x2 and Yxe2x80x2 are independently selected from the group consisting of H, xe2x80x94NH2, xe2x80x94NR2, xe2x80x94NHR, xe2x80x94OH, xe2x80x94SR, xe2x80x94OR and xe2x80x94SH;
R is as previously defined in formula Mxe2x80x2;
RF and p are as defined in formula Lxe2x80x2; and
g) optionally alkylating the compound having formula Gxe2x80x2 to form a compound having formula Hxe2x80x2: 
xe2x80x83wherein
RF and p are as defined in formula Lxe2x80x2;
m and n are independently from about 1 to about 4;
R is as previously defined in formula Mxe2x80x2; and
X and Y are groups capable of partaking in polymerization reactions and are independently selected from the group consisting of xe2x80x94H, xe2x80x94NH2, xe2x80x94NHR, xe2x80x94NR2, xe2x80x94OH, xe2x80x94OR, xe2x80x94SH, xe2x80x94SR, xe2x80x94CO2H, xe2x80x94NCO, 
xe2x80x83wherein
y is about 1 to about 10;
xe2x80x83in order to obtain an unsymmetrically substituted fluorenyl compound having at least one X or Y group selected from the group consisting of xe2x80x94COOH, xe2x80x94NCO, 
The above-mentioned nucleophilic substitution method for producing unsymmetrical 2,7-disubstituted fluoren-9-one derivatives is not only simpler and faster than the previously known methods for doing the same, but it also results in higher product yields. In addition, the cycle time for producing unsymmetrically substituted fluorenyl compounds is also reduced since the second step in its known method of production, see, e.g., ""065 application, may be replaced with the one-step nucleophilic substitution of the present invention.
One aspect of this invention relates to the improved method for preparing unsymmetrical 2,7-disubstituted fluoren-9-one derivatives. In this method, the leaving group Axe2x80x2 in a 2,7-disubstituted fluoren-9-one derivative having formula D is replaced by a nucleophile group, D, as represented by the following general scheme: 
In the above scheme, Axe2x80x2 is a leaving group selected from the group consisting of but not limited to xe2x80x94Br, xe2x80x94Cl, xe2x80x94F, xe2x80x94NO2, and xe2x80x94CN. Preferred leaving groups include xe2x80x94F or xe2x80x94NO2, with xe2x80x94NO2 being the most preferred.
A is a strong electron accepting group which activates the nucleophilic replacement and includes, but is not limited to xe2x80x94NO2, xe2x80x94CN, xe2x80x94CO2R, xe2x80x94C(O)R, xe2x80x94SO2R, xe2x80x94SO2RF, xe2x80x94C(CN)xe2x95x90C(CN)2 and xe2x80x94CHxe2x95x90C(CN)2, wherein
RF is xe2x80x94CpF2p+1,
p is an integer of from about 1 to about 10, preferably about 1 to about 3; and
R is an aromatic group, such as phenyl or napthyl, or a straight, branched or cyclic a aliphatic alkyl group having from about 1 to about 10 carbon atoms.
Preferred electron accepting groups include xe2x80x94CN, xe2x80x94SO2R, xe2x80x94SO2RF and xe2x80x94NO2, with xe2x80x94NO2 being most preferred. 
is a carbonyl or a protected carbonyl such as a ketal or thio-ketal selected from the group consisting of: 
wherein
Rxe2x80x2 is xe2x80x94CrH2r+1;
Rxe2x80x3 is xe2x80x94(CH2)r; and
r is independently an integer of 2 or 3.
Preferably, 
is a ketal, with a 1,3-dioxolane being most preferred.
Suitable nucleophilic reagents are of the formula Dxe2x80x94Z, wherein the D moiety is an electron donating group including, but are not limited to, xe2x80x94NH2, xe2x80x94NHR, xe2x80x94NR2, xe2x80x94OH, xe2x80x94OR, xe2x80x94SH, and xe2x80x94SR. The Z moiety is a metal cation. Preferred D moieties include xe2x80x94NR2, xe2x80x94SH, and xe2x80x94OR, with xe2x80x94NR2 and xe2x80x94OR being most preferred. Preferred Z moieties include lithium, sodium and potassium.
The molar ratio of compounds of formula D to nucleophilic reagents of formula Dxe2x80x94Z is about 1:1-10, and preferably about 1:1.5-5.
In order to facilitate the substitution reaction, aprotic solvents may be used. Suitable solvents include, but are not limited to, diglyme, dimethyl-formamide, dimethylacetamide, N-methylpyrrolidone, and dimethylsulfoxide, with dimethylformamide (xe2x80x9cDMFxe2x80x9d) being preferred.
The substitution reaction of this invention is not limited to the replacement of only one leaving group, such as the Axe2x80x2 moiety, in compounds having formula D. Rather, both the A and Axe2x80x2 group in the precursor compound D may sequentially replaced according to the following brief scheme. This is accomplished by first converting the D group of formula C, which was obtained from the first replacement reaction into an electron acceptor group Axe2x80x3, followed by replacing the remaining A group by the same nucleophilic mechanism. 
wherein
Axe2x80x3 is an electron accepting, weak leaving group selected from xe2x80x94CN, xe2x80x94CO2R, xe2x80x94C(O)R, xe2x80x94SO2R, xe2x80x94SO2RF, xe2x80x94C(CN)xe2x95x90C(CN)2 and xe2x80x94CHxe2x95x90C(CN)2;
R and RF are as previously defined in formula D, and
D has the same definition as D in formula F.
One such transformation is exemplified in the following reaction scheme in which the Dxe2x80x2 in Formula M is xe2x80x94N2R and Axe2x80x3 is xe2x80x94SO2RF: 
The compounds having formulas J and L, respectively, are substantially fluoroalkylated and substantially oxidized, respectively. By xe2x80x9csubstantially fluoroalkylatedxe2x80x9d, it is meant that the xe2x80x94SH group of at least one of the compounds having formula J is fluoroalkylated. By xe2x80x9csubstantially oxidizedxe2x80x9d, it is meant that the xe2x80x94SRF group of at least one compound having formula L is oxidized. Details of fluoroalkylation by RFI on the sulfur atom and subsequent oxidation to a fluoroalkylsulfonyl is well documented in literature. See, e.g., Foss, R. P., et al., 32-3 Polymer Preprints 76 (American Chemical Society 1991); Feiring, A. E. 7 Jour. Fluorine Chem. 191 (1984).
The starting material for the substitution reaction, i.e. compounds having formula D, may be synthesized by methods well known in the art. See, e.g., ""065 Application; Step I infra. All solvents and nucleophilic reagents used in the substitution reactions are commercially available or, in the alternative, may be synthesized by well known methods. Both reagents having the formula, RFI, as well as the oxidation reagents, such as H2O2, Na2O2, CrO3, and the like, are commercially available.
The substitution reaction may be conducted in any conventional reactor at atmospheric pressure.
The temperature at which the substitution reaction is conducted and the period of reaction will depend on the starting material, solvent, and reactant selected. One of ordinary skill in the art can readily optimize the conditions of the reaction without undue experimentation to get the claimed results, but the temperature will generally be in the range of from about 25xc2x0 C. to about 100xc2x0 C., and preferably about 25xc2x0 C. to about 50xc2x0 C., for about 1 to about 24 hours, and preferably from about 1 to about 6 hours.
Another aspect of this invention is directed to a three step process for preparing compounds of formula Bxe2x80x3: 
wherein
Axe2x80x3 is an electron accepting, weak leaving group selected from xe2x80x94CN, xe2x80x94CO2R, xe2x80x94C(O)R, xe2x80x94SO2R, xe2x80x94SO2RF, xe2x80x94C(CN)xe2x95x90C(CN)2 and xe2x80x94CHxe2x95x90C(CN)2; and
R and RF are as previously defined in Formula D.
The first step involves protecting the 9-carbonyl groups of the starting fluorenone derivative, which may be a compound of the formula Dxe2x80x2
The protection reaction involves the reaction of a compound having formula Dxe2x80x2 with a protection reagent in the presence of an acid catalyst and a solvent under conditions sufficient to produce a protected carbonyl compound of the formula E: 
wherein 
is 
Suitable protective reactants may be selected from the group consisting of (CH2OH)2, 
and (CH3O)3CH, with (CH2OH)2 being most preferred.
The starting material for the protection reaction, i.e. compounds of formula Dxe2x80x2, and the reagent are both available from commercial sources. In the protection reaction, the molar ratio of compounds of formula Dxe2x80x2 to the protection reagent is about 1:2-20, preferably about 1:5-10.
Suitable acid catalysts may be selected from the group consisting of hydrogen chloride, hydrogen bromide, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, and fluorosulfonic acid with p-toluenesulfonic acid being preferred. The amount of catalyst used in the protection reaction is, based upon the total moles of the compound having formula Dxe2x80x2, from about 0.001% to about 10%, and preferably about 0.01% to about 1%.
In order to facilitate the protection reaction, a commercially available solvent such as chlorobenzene, dichlorobenzene, and xylene is used. Chlorobenzene is preferred.
The protection reaction may be conducted in any conventional reactor at atmospheric pressure.
The temperature at which the protection reaction is conducted and the period of reaction will depend on the species and amount of starting material, catalyst, solvent, and protective reactant selected. One of ordinary skill in the art can readily optimize the conditions of the reaction without undue experimentation to get the claimed results, but the temperature will generally be in the range of from about 100xc2x0 C. to about 200xc2x0 C., and preferably at the boiling point of the selected solvent, for about 16 to about 100 hours, and preferably from about 24 to about 48 hours.
In the second step, the protected carbonyl compound of formula E: 
is reacted with a nucleophilic reagent in an aprotic solvent to produce an protected 2,7-disubstituted fluoren-9-one derivative having formula F 
wherein 
is 
D is an electron donating group selected from the group consisting of xe2x80x94NH2, xe2x80x94NHR, xe2x80x94NR2, xe2x80x94OH, xe2x80x94OR, xe2x80x94SH, and xe2x80x94SR.
In an alternative embodiment, both xe2x80x94NO2 groups in the precursor compound having formula E may be replaced via the mechanism as exemplified in the following scheme: 
The compounds having formulas Jxe2x80x2 and Lxe2x80x2, respectively, are substantially fluoroalkylated and substantially oxidized, respectively. By xe2x80x9csubstantially fluoroalkylatedxe2x80x9d, it is meant that the xe2x80x94SH group of at least one of the compounds having formula Jxe2x80x2 is fluoroalkylated. By xe2x80x9csubstantially oxidizedxe2x80x9d, it is meant that the xe2x80x94SRF group of at least one compound having formula Lxe2x80x2 is oxidized. Any of the aforementioned oxidation reagents are suitable.
The third step involves deprotection and simultaneous alkylation of the 9-carbonyl group of compounds of formula F or Mxe2x80x2 with active aromatic compounds in the presence of an acid catalyst to yield a 2,7-disubstituted fluorenyl compound geminately alkylated at the 9-carbon having formula Gxe2x80x3: 
wherein
said acid catalyst is of the formula HXxe2x80x3 and said aromatic compounds are of the formula C6H5xe2x80x2, or C6H5Yxe2x80x2, wherein
Axe2x80x3 can be, but is not limited to an electron accepting, weak leaving group selected from xe2x80x94CN, xe2x80x94NO2, xe2x80x94CO2R, xe2x80x94C(O)R, xe2x80x94SO2R, xe2x80x94SO2RF, xe2x80x94C(CN)xe2x95x90C(CN)2 and xe2x80x94CHxe2x95x90C(CN)2; and
R and RF are as previously defined in Formula D;
HXxe2x80x3 is a strong acid such as HCl, HBr, H2SO4, H3PO4, p-toluenesulfonic acid, fluorosulfonic acid; or trifluoromethyl-sulfonic acid; and
Xxe2x80x2 and Yxe2x80x2 are independently selected from the group consisting of xe2x80x94H, xe2x80x94NR2, xe2x80x94OR, xe2x80x94SR, xe2x80x94NH2, xe2x80x94NHR, xe2x80x94SH, xe2x80x94OH;
R is selected from the group consisting of phenyl, naphthyl, and a straight, branched and cyclic aliphatic alkyl group having from about 1 to about 10 carbon atoms;
m and n are independently from about 1 to about 4; and
D is an electron donating group selected from the group consisting of xe2x80x94NH2, xe2x80x94NHR, xe2x80x94NR2, xe2x80x94OH, xe2x80x94OR, xe2x80x94SH, and xe2x80x94SR.
Active aromatic compounds such as phenol, aniline, and monoalkylaniline, are preferred. These active aromatic compounds also serve as solvents for the deprotection reaction. The mole ratio of the compound having formula F or Mxe2x80x2 to the aromatic compound, i.e. phenol, required for the deprotection reaction is about 1:2-20, and preferably about 1:5-10.
Preferable acid catalysts useful in the deprotection reaction include p-toluenesulfonic acid and trifluoromethanesulfonic acid. Although the amount of acid catalyst used may vary widely, it is recommended that about 0.1% to about 10%, and preferably 1% to about 5%, based upon the moles of the starting material used for the deprotection reaction, i.e. the compound having either formula F or Mxe2x80x2, is used.
The aromatic compounds and acid catalysts used in the deprotection reaction are commercially available.
The deprotection and alkylation reaction may be conducted in any conventional reactor at atmospheric pressure.
The temperature at which the deprotection reaction is conducted and the period of reaction will depend on the starting material, i.e. compound having formula F or Mxe2x80x2, acid catalyst, and aromatic compound reactant selected. One of ordinary skill in the art can readily optimize the conditions of the reaction without undue experimentation to get the claimed results, but the temperature will generally be in the range of from about 50xc2x0 C. to about 150xc2x0 C., and preferably about 50xc2x0 C. to about 100xc2x0 C., for about 2 to about 24 hours, and preferably from about 6 to about 12 hours.
In order to obtain compounds having formula Hxe2x80x3 wherein the X or Y groups are other than the Xxe2x80x2 or Yxe2x80x2 groups provided in formula Gxe2x80x3, it is necessary to functionally transform the compound having formula Gxe2x80x3 into a compound having formula Hxe2x80x3
wherein
Axe2x80x3 can be, but is not limited to an electron accepting, weak leaving group selected from xe2x80x94CN, xe2x80x94NO2, xe2x80x94CO2R, xe2x80x94C(O)R, xe2x80x94SO2R, xe2x80x94SO2RF, xe2x80x94C(CN)xe2x95x90C(CN)2 and xe2x80x94CHxe2x95x90C(CN)2; and
R and RF are as previously defined in Formula D;
D is an electron donating group selected from the group consisting of xe2x80x94NH2, xe2x80x94HR, xe2x80x94NR2, xe2x80x94OH, xe2x80x94OR, xe2x80x94SH, and xe2x80x94SR;
X and Y are independently selected from the group consisting of xe2x80x94H, xe2x80x94NH2, xe2x80x94NHR, xe2x80x94NR2, xe2x80x94OH, xe2x80x94OR, xe2x80x94SH, xe2x80x94SR, xe2x80x94COOH, xe2x80x94NCO, 
m and n are independently from about 1 to about 4; and
y is an integer from about 1 to about 10.
xe2x80x83via a conventional alkylation procedure. Such conventional alkylation procedures are well known in the literature. See, e.g., Sandler, S. R., et al., H(5, 9, 10, 17) and III(5) Organic Functional Group Preparations (2nd ed 1983); Sandler, S. R. et al., II(3) Polymer Syntheses(1977); Larcock, R. C., Comprehensive Organic Transformations, (1989).